Comparative Pharmacokinetic, Pharmacodynamic, Safety and Efficacy Study of Three Anti-CD20 Monoclonal Antibodies in Patients With Moderate to Severe Rheumatoid Arthritis

This study will compare the plasma pharmacokinetic profile and the change in disease activity score in patients with active rheumatoid arthritis following treatment with two 1000 mg doses of DRL_RI or one of two sources of rituximab (Rituxan® or MabThera®). Patients will also be monitored for safety, B cell depletion and recovery, and for the development of immune responses to the administered study drugs

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Biological: DRL_RI; Biological: Rituxan; Biological: MabThera

• Study Type: Interventional
• Enrollment (Actual): 276
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• India
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500020
      • Gurunank Care Hospital
    • Hyderabad, Andhra Pradesh, India, 500034
      • Care Hospitals
    • Secunderabad, Andhra Pradesh, India, 500003
      • Krishna Institute of Medical Sciences Ltd.
  • Andhra Predesh
    • Secunderabad, Andhra Predesh, India, 500003
      • Yashoda Hospital
  • Delhi
    • New Delhi, Delhi, India, 110002
      • Maulana Azad Medical College & Associated Lok Nayak Hospitals
    • New Delhi, Delhi, India, 110076
      • lndraprastha Apollo Hospitals
  • Gujarat
    • Ahmedabad, Gujarat, India, 380015
      • Shalby Hospitals
    • Surat, Gujarat, India, 395001
      • Government Medical College & New Civil Hospital
  • Karnataka
    • Bangalore, Karnataka, India, 560079
      • Chanre Rheumatology & Immunology Center & Research
    • Hubli, Karnataka, India, 5880021
      • Sushruta Multispeciality Hospital & Research Centre Pvt. Ltd
    • Mysore, Karnataka, India, 570004
      • Jagadguru Sri Shivarathreeshwara Hospital
  • Maharashtra
    • Mumbai, Maharashtra, India, 400053
      • Kokilaben Dhirubhai Ambani Hospital & Medical Research Institute
    • Pune, Maharashtra, India, 411001
      • Jehangir Clinical Development Centre Pvt. Ltd.
    • Pune, Maharashtra, India, 411005
      • Oyster & Pearl Hospital
    • Pune, Maharashtra, India, 411004
      • Deennath Mangeshkar Hospital and Research Centre
    • Pune, Maharashtra, India, 411040
      • lnamdar Multispeciality Hospital
  • Punjab
    • Ludhiana, Punjab, India, 141001
      • Dayanand Medical College & Hosptial
  • Rajasthan
    • Jaipur, Rajasthan, India, 302001
      • S. R. Kalla Memorial Gastro & General Hospital
    • Jaipur, Rajasthan, India, 302006
      • Shri Nidaan Hospital & Hope Fertility Centre
  • Tamil Nadu
    • Madurai, Tamil Nadu, India, 625020
      • Apollo Specialty Hosptials
  • Uttar Pradesh
    • Lucknow, Uttar Pradesh, India, 226018
      • King George's Medical University
• Ukraine
  • Kharkiv, Ukraine, 61176
    • Communal Healthcare Institution Kharkiv City Clinical Hospital #8
  • Kyiv, Ukraine, 03680
    • State Institution National Scientific Center Acad. Strazhesko Institute of Cardiology of National Academy of Medical Science
  • Kyiv, Ukraine, 04114
    • State Institution D.F. Chebotariov Institute of Gerontology of NAMS of Ukraine
  • Poltava, Ukraine, 36011
    • M.V. Sklifosovskyi Poltava Regional Clinical Hospital
  • Vinnytsia, Ukraine, 21018
    • Vinnytsia M.I. Pyrogov Regional Clinical Hospital
  • Vinnytsia, Ukraine, 21029
    • Medical Clinical Investigational Center MC LLC Health Clinic
  • Zaporizhzhia, Ukraine, 69600
    • Communal Institution Zaporzhzhia Regional Clinical Hospital of Zaporizhzhia Regional Council

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patients, 18 to 65 years of age
2. Diagnosis of RA, according to ACR criteria (1987), of at least 6 months duration
3. At randomization, tender joint count ≥ 6 and swollen joint count ≥ 6
4. Evidence of at least moderate disease activity
5. Patients receiving oral or parenteral MTX with a dose of 15 to 25 mg per week when given alone or 10 to 25 mg per week in combination with additional non-biologic DMARD(s) for at least 6 months and on stable dose for at least 3 months
6. Patients must be on a stable dose of folic acid or equivalent (≥5 mg per week)
7. Chest X-ray not suggestive of any lung infections including pulmonary tuberculosis (TB)
8. Contraception required per protocol

Exclusion Criteria:

1. Prior therapy with

   • Rituximab, abatacept, tocilizumab, anakinra or an agent/antibody targeting CD20, CD19 or B cells
   • Tumor necrosis factor (TNF) alfa antagonists or other biologic DMARDs

   Other prior or concurrent therapies may also be excluded

2. Any clinically relevant abnormality detected on screening history, physical examination, clinical laboratory, chest X-ray, or electrocardiogram (ECG), other than values consistent with RA
3. Evidence of active, suspected or inadequately treated TB
4. Positive serological test for hepatitis C virus antibodies, hepatitis B surface antigen, hepatitis B core antibody, or human immunodeficiency virus
5. History of cardiovascular disease, history of stroke, or uncontrolled hypertension
6. History of lymphoproliferative disease or organ allograft
7. History of cancer (except for in situ cancer, excised, or limited stage, curatively treated cancer with no sign of disease for >5 years)
8. History of allergy (medication history) to any of the compounds used in the study
9. Pregnant or lactating women or women planning to become pregnant during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: MabThera	Biological: MabThera; Two 1000 mg intravenous infusions, one each on Day 1 and Day 15; Other Names: Rituximab
Active Comparator: Rituxan	Biological: Rituxan; Two 1000 mg intravenous infusions, one each on Day 1 and Day 15; Other Names: Rituximab
Experimental: DRL_RI	Biological: DRL_RI; Two 1000 mg intravenous infusions, one each on Day 1 and Day 15

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration-Time Curve From Time 0 to 336 Hours (AUC0-336) Post First Dose	PK samples were collected pre-infusion; 3 hours post infusion; EOI; and at 1, 6, 24, 48, 168 hours post End of Infusion. A PK sample at 336 hours post EOI were also to be collected after the second dose.	2 weeks
AUC0-∞ Over the Entire Course of Therapy (2 Doses) From Day 1 Through Week 16.	PK samples were collected pre-infusion; 3 hours post infusion; EOI; and at 1, 6, 24, 48, 168 hours post End of Infusion. A PK sample at 336 hours post EOI were also to be collected after the second dose.	16 weeks
Area Under Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-t) (Second Dose).	PK samples were collected pre-infusion; 3 hours post infusion; EOI; and at 1, 6, 24, 48, 168 hours post End of Infusion. A PK sample at 336 hours post EOI were also to be collected after the second dose	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentration (Cmax) After First Dose	Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) ,and 168 hours (post-EOI).	2 weeks
Maximum Plasma Concentration (Cmax) After Second Dose	Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI),6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , 168 (post-EOI), and 336 hours post EOI.	2 weeks
Time to Cmax (Tmax) After First Dose.	Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , and 168 hours (post-EOI).	2 weeks
Time to Cmax (Tmax) After Second Dose	Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , and 168 hours (post-EOI).	2 weeks
Volume of Distribution (Vz)	Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , 168 (post-EOI), 336 hours (post-EOI), 4 weeks, 6 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, and 22 weeks relative to infusion.	24 weeks
Systemic Clearance (CL)	Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , 168 (post-EOI), 336 hours (post-EOI), 4 weeks, 6 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, and 22 weeks relative to infusion.	24 weeks
Terminal Half-life (t1/2)	Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , 168 (post-EOI), 336 hours (post-EOI), 4 weeks, 6 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, and 22 weeks relative to infusion.	24 weeks
Mean Change in Disease Activity Score-C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Weeks 4	In clinical studies, Disease Activity Score (DAS) is used to assess improvement in disease activity in RA patients over time. The assessment involved an examination of 28 joints for swelling, tenderness, blood C-reactive protein (CRP), and a one on one consultation between the patient and healthcare professional. The results were combined to produce a score which indicated how active the RA was at that particular time. The disease activity is interpreted as low (DAS <2.6), mild (2.6 to <3.2), moderate (3.2 to <5.1), and severe with DAS > 5.1. A DAS score between 0 and 2.6 corresponds to remission. The analysis of DAS28-CRP was based on a generalized estimating equation model in RA patients with DAS28 score > 3.2. The mean change was calculated from two time points (Value at 4 weeks minus baseline value).	Baseline and 4 weeks
Mean Change in DAS28-CRP From Baseline Per Unit Time at 8 Weeks.	In clinical studies, Disease Activity Score (DAS) is used to assess improvement in disease activity in RA patients over time. The assessment involved an examination of 28 joints for swelling, tenderness, blood C-reactive protein (CRP), and a one on one consultation between the patient and healthcare professional. The results were combined to produce a score which indicated how active the RA was at that particular time. The disease activity is interpreted as low (DAS <2.6), mild (2.6 to <3.2), moderate (3.2 to <5.1), and severe with DAS > 5.1. A DAS score between 0 and 2.6 corresponds to remission. The analysis of DAS28-CRP was based on a generalized estimating equation model in RA patients with DAS28 score > 3.2. The mean change was calculated from two time points (Value at 8 weeks minus baseline value).	Baseline and 8 weeks
Mean Change in DAS28-CRP From Baseline Per Unit Time at Week 12.	In clinical studies, Disease Activity Score (DAS) is used to assess improvement in disease activity in RA patients over time. The assessment involved an examination of 28 joints for swelling, tenderness, blood C-reactive protein (CRP), and a one on one consultation between the patient and healthcare professional. The results were combined to produce a score which indicated how active the RA was at that particular time. The disease activity is interpreted as low (DAS <2.6), mild (2.6 to <3.2), moderate (3.2 to <5.1), and severe with DAS > 5.1. A DAS score between 0 and 2.6 corresponds to remission. The analysis of DAS28-CRP was based on a generalized estimating equation model in RA patients with DAS28 score > 3.2. The mean change was calculated from two time points (Value at 12 weeks minus baseline value).	Baseline and 12 weeks
Mean Change in Disease Activity Score- C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Week 16.	In clinical studies, Disease Activity Score (DAS) is used to assess improvement in disease activity in RA patients over time. The assessment involved an examination of 28 joints for swelling, tenderness, blood C-reactive protein (CRP), and a one on one consultation between the patient and healthcare professional. The results were combined to produce a score which indicated how active the RA was at that particular time. The disease activity is interpreted as low (DAS <2.6), mild (2.6 to <3.2), moderate (3.2 to <5.1), and severe with DAS > 5.1. A DAS score between 0 and 2.6 corresponds to remission. The analysis of DAS28-CRP was based on a generalized estimating equation model in RA patients with DAS28 score > 3.2. The mean change was calculated from two time points (Value at 16 weeks minus baseline value).	Baseline and 16 weeks
Percentage of Patients With B-cell Counts 20% Below the Lower Limit of Normal	The time to depletion and repletion of peripheral blood cell counts (determined by CD19+ cell counts) as well as the B-cell counts at selected time points (taking into consideration the patient baseline count) were used to assess the PD of the study drugs.	48 hours
Percentage of Patients With Peripheral B-cell Counts Depletion at Week 16.	Analysis of the PD parameter peripheral B-Cell count was performed by evaluating the 95% CI for the difference between treatment arms in the percentage of patients with B-cell depletion at 48 hours after dose 1, Week 16, and at Week 24. Percentage of patients with B-cell repletion at each evaluation time is also reported and descriptively compared.	16 weeks
Percentage of Patients With Peripheral B-cell Counts Depletion at Week 24.	Analysis of the PD parameter peripheral B-Cell count was performed by evaluating the 95% CI for the difference between treatment arms in the percentage of patients with B-cell depletion at 48 hours after dose 1, Week 16, and at Week 24. Percentage of patients with B-cell repletion at each evaluation time is also reported and descriptively compared.	24 weeks
Percentage of Patients With ACR20 at Week 24	Percentage of the patients with at least 20% improvement in counts of tender, swollen joints and in 3 of the following: patient's assessment of pain, patient's global assessment of disease activity, patient's assessment of physical function, the physician's global assessment of disease activity, and acute phase reactant. Adjusted response rates for the treatment arms using the logistic regression analysis including treatment, gender and region as fixed effects and patients as random effect in the model.	24 weeks
Percentage of Patients With ACR50 at Week 24	Percentage of the patients with at least 50% improvement in counts of tender, swollen joints and in 3 of the following: patient's assessment of pain, patient's global assessment of disease activity, patient's assessment of physical function, the physician's global assessment of disease activity, and acute phase reactant. Adjusted Response rates for the treatment arms using the logistic regression analysis including treatment, gender and region as fixed effects and patients as random effect in the model.	24 weeks
Percentage of Patients With ACR70 Response at Week 24	Percentage of the patients with at least 70% improvement in counts of tender, swollen joints and in 3 of the following: patient's assessment of pain, patient's global assessment of disease activity, patient's assessment of physical function, the physician's global assessment of disease activity, and acute phase reactant. Adjusted Response rates for the treatment arms using the logistic regression analysis including treatment, gender and region as fixed effects and patients as random effect in the model.	24 weeks
Change From Baseline in HAQ-DI at Week 24.	The health assessment questionnaire disability index (HAQ-DI) was assessed at Week 24. The disability assessment component of the HAQ, the HAQ-DI, assessed a patient's level of functional ability and included questions about fine movements of the upper extremities, locomotor activities of the lower extremities, and activities that involved both upper and lower extremities. There were 20 questions in 8 categories of functioning which represented a comprehensive set of functional activities-dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. The stem of each item asked over the past week "Were you able to" perform a particular task. The patient's responses were made on a scale from 0 (no disability) to 3 (completely disabled). Each category contained at least 2 specific component questions. Physical function was measured using the HAQ-DI Scores, which range from 0-3, with lower scores reflecting better physical function and thus, less disability.	24 weeks

Collaborators and Investigators

• Sponsor: Dr. Reddy's Laboratories Limited

Publications and helpful links

General Publications

• Haridas VM, Katta R, Nalawade A, Kharkar S, Zhdan V, Garmish O, Lopez-Lazaro L, Batra SS, Kankanwadi S. Pharmacokinetic Similarity and Comparative Pharmacodynamics, Safety, Efficacy, and Immunogenicity of DRL_RI Versus Reference Rituximab in Biologics-Naive Patients with Moderate-to-Severe Rheumatoid Arthritis: A Double-Blind, Randomized, Three-Arm Study. BioDrugs. 2020 Apr;34(2):183-196. doi: 10.1007/s40259-020-00406-1.

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): October 5, 2017

Study Registration Dates

• First Submitted: November 18, 2014
• First Submitted That Met QC Criteria: November 18, 2014
• First Posted (Estimate): November 20, 2014

Study Record Updates

• Last Update Posted (Actual): January 13, 2020
• Last Update Submitted That Met QC Criteria: December 27, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Rituximab; Rheumatoid arthritis
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: RI-01-003